Women at highest breast cancer risk are those with inherited mutations in breast cancer genes, such as BRCA1. We will identify BRCA1 carriers among population-based breast cancer cases and their relatives enrolled in the Cooperative Family Registry for Breast Cancer Studies (CFRBCS). Approximately 6,300 breast cancer cases and 30,000 of their relatives are being accrued; one-half are statistically sampled from 3 population-based cancer registries. Each breast cancer case has consented to respond to standard questionnaires on family history, diet, and other breast cancer risk factors. Blood specimens to generate DNA and follow-up data are also being collected on probands, affected relatives and other selected family members. This Registry of a large number of well-characterized subjects provides exceptional opportunities for genetic studies of breast cancer. Our 3 specific research aims are to use an efficient detection strategy to estimate population-based BRCA1 mutation frequency and age-specific penetrance in 2,036 CFRBCS breast cancer families. Secondly, by exchanging 220 coded samples, 3 independent CFRBCS laboratories (ours and 2 others) will test the analytical validity (sensitivity and specificity) of various mutation detection technologies. Lastly, subgroups of population-based families will be categorized by BRCA1 mutation type (truncating/non-truncating) and position, and tested for differences in frequency of cancers of the breast, ovary, prostate, and colon. These results will lead to future studies of modifying effects on BRCA1 carriers of hormone-related risk factors (ages at menarche, first full-term pregnancy, menopause, and exogenous estrogen use), smoking, alcohol use, and ionizing radiation. Our validated BRCA1 data will be submitted to the CFRBCS Central Database for investigations of early intervention strategies and cancer outcomes among BRCA1 carriers.